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Background: It has been demonstrated that cognitive behavioural therapy (CBT) has a moderate effect on symptom reduction and on general well being of patients suffering from psychosis. However, questions regarding the specific efficacy of CBT, the treatment safety, the cost-effectiveness, and the moderators and mediators of treatment effects are still a major issue. The major objective of this trial is to investigate whether CBT is specifically efficacious in reducing positive symptoms when compared with non-specific supportive therapy (ST) which does not implement CBT-techniques but provides comparable therapeutic attention. Methods: The POSITIVE study is a multicenter, prospective, single-blind, parallel group, randomised clinical trial, comparing CBT and ST with respect to the efficacy in reducing positive symptoms in psychotic disorders. CBT as well as ST consist of 20 sessions altogether, 165 participants receiving CBT and 165 participants receiving ST. Major methodological aspects of the study are systematic recruitment, explicit inclusion criteria, reliability checks of assessments with control for rater shift, analysis by intention to treat, data management using remote data entry, measures of quality assurance (e.g. on-site monitoring with source data verification, regular query process), advanced statistical analysis, manualized treatment, checks of adherence and competence of therapists. Research relating the psychotherapy process with outcome, neurobiological research addressing basic questions of delusion formation using fMRI and neuropsychological assessment and treatment research investigating adaptations of CBT for adolescents is combined in this network. Problems of transfer into routine clinical care will be identified and addressed by a project focusing on cost efficiency. Discussion: This clinical trial is part of efforts to intensify psychotherapy research in the field of psychosis in Germany, to contribute to the international discussion on psychotherapy in psychotic disorders, and to help implement psychotherapy in routine care. Furthermore, the study will allow drawing conclusions about the mediators of treatment effects of CBT of psychotic disorders. Trial Registration Current Controlled Trials ISRCTN29242879
Background In October 2007, the working group CEN/TC 216 of the European Committee for standardisation suggested that the Sabin oral poliovirus vaccine type 1 strain (LSc-2ab) presently used for virucidal tests should be replaced by another attenuated vaccine poliovirus type 1 strain, CHAT. Both strains were historically used as oral vaccines, but the Sabin type 1 strain was acknowledged to be more attenuated. In Germany, vaccination against poliomyelitis was introduced in 1962 using the oral polio vaccine (OPV) containing Sabin strain LSc-2ab. The vaccination schedule was changed from OPV to an inactivated polio vaccine (IPV) containing wild polio virus type 1 strain Mahoney in 1998. In the present study, we assessed potential differences in neutralising antibody titres to Sabin and CHAT in persons with a history of either OPV, IPV, or OPV with IPV booster. Methods Neutralisation poliovirus antibodies against CHAT and Sabin 1 were measured in sera of 41 adults vaccinated with OPV. Additionally, sera from 28 children less than 10 years of age and immunised with IPV only were analysed. The neutralisation assay against poliovirus was performed according to WHO guidelines. Results The neutralisation activity against CHAT in adults with a complete OPV vaccination series was significantly lower than against Sabin poliovirus type 1 strains (Wilcoxon signed-rank test P < 0.025). In eight sera, the antibody titres measured against CHAT were less than 8, although the titre against Sabin 1 varied between 8 and 64. Following IPV booster, anti-CHAT antibodies increased rapidly in sera of CHAT-negative adults with OPV history. Sera from children with IPV history neutralised CHAT and Sabin 1 strains equally. Conclusion The lack of neutralising antibodies against the CHAT strain in persons vaccinated with OPV might be associated with an increased risk of reinfection with the CHAT polio virus type 1, and this implies a putative risk of transmission of the virus to polio-free communities. We strongly suggest that laboratory workers who were immunised with OPV receive a booster vaccination with IPV before handling CHAT in the laboratory.
Hepatitis C virus (HCV) naturally infects only humans and chimpanzees. The determinants responsible for this narrow species tropism are not well defined. Virus cell entry involves human scavenger receptor class B type I (SR-BI), CD81, claudin-1 and occludin. Among these, at least CD81 and occludin are utilized in a highly species-specific fashion, thus contributing to the narrow host range of HCV. We adapted HCV to mouse CD81 and identified three envelope glycoprotein mutations which together enhance infection of cells with mouse or other rodent receptors approximately 100-fold. These mutations enhanced interaction with human CD81 and increased exposure of the binding site for CD81 on the surface of virus particles. These changes were accompanied by augmented susceptibility of adapted HCV to neutralization by E2-specific antibodies indicative of major conformational changes of virus-resident E1/E2-complexes. Neutralization with CD81, SR-BI- and claudin-1-specific antibodies and knock down of occludin expression by siRNAs indicate that the adapted virus remains dependent on these host factors but apparently utilizes CD81, SR-BI and occludin with increased efficiency. Importantly, adapted E1/E2 complexes mediate HCV cell entry into mouse cells in the absence of human entry factors. These results further our knowledge of HCV receptor interactions and indicate that three glycoprotein mutations are sufficient to overcome the species-specific restriction of HCV cell entry into mouse cells. Moreover, these findings should contribute to the development of an immunocompetent small animal model fully permissive to HCV.
HDL, through sphingosine-1-phosphate (S1P), exerts direct cardioprotective effects on ischemic myocardium. It remains unclear whether other HDL-associated sphingophospholipids have similar effects. We therefore examined if HDL-associated sphingosylphosphorylcholine (SPC) reduces infarct size in a mouse model of transient myocardial ischemia/reperfusion. Intravenously administered SPC dose-dependently reduced infarct size after 30 minutes of myocardial ischemia and 24 hours reperfusion compared to controls. Infarct size was also reduced by postischemic, therapeutical administration of SPC. Immunohistochemistry revealed reduced polymorphonuclear neutrophil recruitment to the infarcted area after SPC treatment, and apoptosis was attenuated as measured by TUNEL. In vitro, SPC inhibited leukocyte adhesion to TNFα-activated endothelial cells and protected rat neonatal cardiomyocytes from apoptosis. S1P3 was identified as the lysophospholipid receptor mediating the cardioprotection by SPC, since its effect was completely absent in S1P3-deficient mice. We conclude that HDL-associated SPC directly protects against myocardial reperfusion injury in vivo via the S1P3 receptor.
Leukotrienes constitute a group of bioactive lipids generated by the 5-lipoxygenase (5-LO) pathway. An increasing body of evidence supports an acute role for 5-LO products already during the earliest stages of pancreatic, prostate, and colorectal carcinogenesis. Several pieces of experimental data form the basis for this hypothesis and suggest a correlation between 5-LO expression and tumor cell viability. First, several independent studies documented an overexpression of 5-LO in primary tumor cells as well as in established cancer cell lines. Second, addition of 5-LO products to cultured tumor cells also led to increased cell proliferation and activation of anti-apoptotic signaling pathways. 5-LO antisense technology approaches demonstrated impaired tumor cell growth due to reduction of 5-LO expression. Lastly, pharmacological inhibition of 5-LO potently suppressed tumor cell growth by inducing cell cycle arrest and triggering cell death via the intrinsic apoptotic pathway. However, the documented strong cytotoxic off-target effects of 5-LO inhibitors, in combination with the relatively high concentrations of 5-LO products needed to achieve mitogenic effects in cell culture assays, raise concern over the assignment of the cause, and question the relationship between 5-LO products and tumorigenesis. Keywords: leukotriene, apoptosis, cell proliferation, mitogenic effects, cytotoxicity
Introduction: The Vbeta12-transgenic mouse was previously generated to investigate the role of antigen-specific T cells in collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis. This mouse expresses a transgenic collagen type II (CII)-specific T-cell receptor (TCR) beta-chain and consequently displays an increased immunity to CII and increased susceptibility to CIA. However, while the transgenic Vbeta12 chain recombines with endogenous alpha-chains, the frequency and distribution of CII-specific T cells in the Vbeta12-transgenic mouse has not been determined. The aim of the present report was to establish a system enabling identification of CII-specific T cells in the Vbeta12-transgenic mouse in order to determine to what extent the transgenic expression of the CII-specific beta-chain would skew the response towards the immunodominant galactosylated T-cell epitope and to use this system to monitor these cells throughout development of CIA. Methods: We have generated and thoroughly characterized a clonotypic antibody, which recognizes a TCR specific for the galactosylated CII(260-270) peptide in the Vbeta12-transgenic mouse. Hereby, CII-specific T cells could be quantified and followed throughout development of CIA, and their phenotype was determined by combinatorial analysis with the early activation marker CD154 (CD40L) and production of cytokines. Results: The Vbeta12-transgenic mouse expresses several related but distinct T-cell clones specific for the galactosylated CII peptide. The clonotypic antibody could specifically recognize the majority (80%) of these. Clonotypic T cells occurred at low levels in the naïve mouse, but rapidly expanded to around 4% of the CD4+ T cells, whereupon the frequency declined with developing disease. Analysis of the cytokine profile revealed an early Th1-biased response in the draining lymph nodes that would shift to also include Th17 around the onset of arthritis. Data showed that Th1 and Th17 constitute a minority among the CII-specific population, however, indicating that additional subpopulations of antigen-specific T cells regulate the development of CIA. Conclusions: The established system enables the detection and detailed phenotyping of T cells specific for the galactosylated CII peptide and constitutes a powerful tool for analysis of the importance of these cells and their effector functions throughout the different phases of arthritis.
The role of gamma oscillatory activity in magnetoencephalogram for auditory memory processing
(2010)
Recent studies have suggested an important role of cortical gamma oscillatory activity (30-100 Hz) as a correlate of encoding, maintaining and retrieving auditory, visual or tactile information in and from memory. It was shown that these cortical stimulus representations were modulated by attention processes. Gamma-band activity (GBA) occurred as an induced response peaking at approximately 200-300 ms after stimulus presentation. Induced cortical responses appear as non-phase-locked activity and are assumed to reflect active cortical processing rather than passive perception. Induced GBA peaking 200-300 ms after stimulus presentation has been assumed to reflect differences between experimental conditions containing various stimuli. By contrast, the relationship between specific oscillatory signals and the representation of individual stimuli has remained unclear. The present study aimed at the identification of such stimulus-specific gamma-band components. We used magnetoencephalography (MEG) to assess gamma activity during an auditory spatial delayed matching-to-sample task. 28 healthy adults were assigned to one of two groups R and L who were presented with only right- or left-lateralized sounds, respectively. Two sample stimuli S1 with lateralization angles of either 15° or 45° deviation from the midsagittal plane were used in each group. Participants had to memorize the lateralization angle of S1 and compare it to a second lateralized sound S2 presented after an 800-ms delay phase. S2 either had the same or a different lateralization angle as S1. After the presentation of S2, subjects had to indicate whether S1 and S2 matched or not. Statistical probability mapping was applied to the signals at sensor level to identify spectral amplitude differences between 15° and 45° stimuli. We found distinct gamma-band components reflecting each sample stimulus with center frequencies ranging between 59 and 72 Hz in different sensors over parieto-occipital cortex contralateral to the side of stimulation. These oscillations showed maximal spectral amplitudes during the middle 200-300 ms of the delay phase and decreased again towards its end. Additionally, we investigated correlations between the activation strength of the gamma-band components and memory task performance. The magnitude of differentiation between oscillatory components representing 'preferred' and 'nonpreferred' stimuli during the final 100 ms of the delay phase correlated positively with task performance. These findings suggest that the observed gamma-band components reflect the activity of neuronal networks tuned to specific auditory spatial stimulus features. The activation of these networks seems to contribute to the maintenance of task-relevant information in short-term memory.
Despite sensible guidelines for the use of opioid analgesics, respiratory depression remains a significant risk with a possibility of fatal outcomes. Clinicians need to find a balance of analgesia with manageable respiratory effects. The ampakine CX717 (Cortex Pharmaceuticals, Irvine, CA, USA), an allosteric enhancer of glutamate-stimulated AMPA receptor activation, has been shown to counteract opioid-induced respiratory depression in rats while preserving opioid-induced analgesia. Adopting a translational approach, we orally administered 1500 mg of CX717 to 16 male healthy volunteers in a placebo controlled double-blind study. Starting 100 min after CX717 or placebo intake, alfentanil was administered by computerized intravenous infusion targeting a plateau of effective alfentanil plasma concentrations of 100 ng/ml. One hour after start of opioid infusion, its effects were antagonized by intravenous injection of 1.6 mg of the classical opioid antidote naloxone. Respiration was quantified prior to drug administration (baseline), during alfentanil infusion and after naloxone administration by (i) counting the spontaneous respiratory frequency at rest and (ii) by employing hypercapnic challenge with CO2 rebreathing that assessed the expiratory volume at a carbon dioxide concentration in the breathable air of 55% (VE55). Pain was quantified at the same time points, immediately after assessment of respiratory parameters, by (i) measuring the tolerance to electrical stimuli (5 Hz sine increased by 0.2 mA/s from 0 to 20 mA and applied via two gold electrodes placed on the medial and lateral side of the mid-phalanx of the right middle finger) and (ii) by measuring the tolerance to heat (increased by 0.3°C/s from 32 to 52.5°C applied to a 3 x 3 cm2 skin area of the left volar forearm, after sensitization with 0.15 g capsaicin cream 0.1%). CX717 was tolerated by all subjects without side effects that would have required medical intervention. We observed that CX717 was approximately as effective as naloxone in reversing the opioid induced reduction of the respiratory frequency. Despite the presence of high plasma alfentanil concentrations, the respiratory frequency decreased only by 8.9 ± 22.4% when CX717 was pre-administered, which was comparable to the 7.0 ± 19.3% decrease observed after administration of naloxone. In contrast, after placebo pre-administration the respiratory rate decreased by 30.0 ± 21.3% (p=0.0054 for CX717 versus placebo). In agreement with this, periods of a very low respiratory frequency of <= 4 min-1 under alfentanil alone were shortened by ampakine pre-dosing by 52.9% (p=0.0182 for CX717 versus placebo). Furthermore, VE55 was decreased during alfentanil infusion by 55.9 ± 16.7% under placebo preadministration but only by 46.0 ± 18.1% under CX717 pre-administration (p=0.017 for CX717 versus placebo). Most importantly, in contrast to naloxone, CX717 had no effect on opioid induced analgesia. Alfentanil increased the pain tolerance to electrical stimuli by 68.7 ± 59.5% with placebo pre-administration. With CX717 pre-administration, the increase of the electrical pain tolerance was similar (54.6 ± 56.7%, p=0.1 for CX717 versus placebo). Similarly, alfentanil increased the heat pain tolerance threshold by 24.6 ± 10.0% with placebo pre-administration. Ampakine co-administration had also no effect on the increase of the heat pain tolerance of the capsaicin-sensitized skin (23.1 ± 8.3%, p=0.46 for CX717 versus placebo). The results of this study allow us to draw the conclusion, that opioid induced ventilatory depression can be selectively antagonized in humans by co-administering an ampakine. This is the first successful translation of a selective antagonism of opioidinduced respiratory depression from animal research into application in humans. Ampakines, namely CX717, thus are the first selective antidote for opioid-induced respiratory depression without loss of analgesia, available for the use in humans.
The physiology of our most complex organ, the brain, is still not comprehensively understood. The brain basically serves the processing, storing and binding of external and internal information, and thereby generates amazing phenomena like the understanding of oneself as an individual entitiy. How exactly information is encoded and represented, how individual neurons or networks of neurons actually interact, is a gigantic puzzle, whose pieces were collected since many decades. Subject of scientific discussions are the basic spatiotemporal structures of neuronal representations. Suggestions and observations reach hereby from simple rate coding of individual neurons to synchronous activity of larger ensembles. To approach answers to these questions, our working group has used a combination of different recording techniques that allowed for the comparison of neuronal interactions on different spatial scales. We focused on prefrontal neuronal interactions during visual short-term memory. Herefore two rhesus monkeys had been trained to perform a visual short-term memory task. We measured and recorded their neuronal activity by means of a microelectrode matrix that could be inserted into the cortex via a closable chamber, which had been previously implanted above prefrontal cortex. The acquired signal was separated into two components: a high-frequency component, that represents the spiking output activity of few neurons in the vicinity of each electrode tip (multi-unit activity), and a low-frequency component, that results from dendritic input activity of larger neuronal assemblies (local field potential). From one of the experimental animals we also recorded mass signals of even larger neuronal populations by means of small silverball electrodes, that had been implated into the skull above prefrontal cortex (skull EEG) in the context of a pilot project. In the first subproject, we analyzed the selectivity of output signals with respect to the memorized stimulus and task performance. We compared selectivities of local recording sites (multi-unit activity) with the selectivities of patterns created by the combined activity of all recording sites, thus representing the activity of large and distributed ensembles. Local neuronal activity correlated with the course of the visual short-term memory task, but was not highly discriminative with respect to different visual stimuli. We could show that the population activity was significantly more specific. Concerning task performance, we obtained the same result, albeit less pronounced. Further analyses revealed that the patterns of distributed ensemble activity were only partly based on realtime coordination of neuronal activity, and in addition, did not remain stable across the time course of the short-term memory task. In the second subproject, we focused on the oscillatory behavior of the local field potential. After a time-frequency analysis, we studied different frequency bands concerning stimulus selectivity and task performance of the monkey. We hereby found significant modulations of oscillations in the beta- and gamma-frequency range, that correlated with different periods of the task. Especially for oscillations in beta- and low-gamma-range, we observed phase-locking of oscillations between different recording sites, which could play an important role as internal clock to coordinate spatially separate activity. Local high-gamma oscillations themselves seemed to be important for the maintenance of information. These results could be partly confirmed by mass signals of EEG. In sum, our results support the hypothesis that information is represented in the brain by means of concerted activity of spatially distributed neuronal ensembles. This activity again appears to be coordinated by oscillatory activity in beta- and low-gamma-frequency ranges. A deeper understanding of central nervous information processing could contribute to better treatment of diseases like Parkinson’s, Alzheimer’s as well as epilepsy, and neuropsychiatric disorders like schizophrenia.
Twin and family studies in autistic disorders (AD) have elucidated a high heritability of AD. In this literature review, we will present an overview on molecular genetic studies in AD and highlight the most recent findings of an increased rate of copy number variations in AD. An extensive literature search in the PubMed database was performed to obtain English published articles on genetic findings in autism. Results of linkage, (genome wide) association and cytogenetic studies are presented, and putative aetiopathological pathways are discussed. Implications of the different genetic findings for genetic counselling and genetic testing at present will be described. The article ends with a prospectus on future directions. Keywords: Autistic disorder , Linkage , Whole genome association , Copy number variation , Mutation